Blood flow diagnostic method

ABSTRACT

A diagnostic method intended primarily for the evaluation of velocity-related abnormalities in blood. These conditions are determined by sensing the inherent tendency of blood red cells to modulate the amplitude of an electric current at a distance from the electrodes. Resulting variations in electrical impedance follow an invariable cube-root function of corpuscle velocity. Electrode configuration and placement are essential factors. The electrodes employed are specially adapted for the measurement of velocity in very small vesssels or hollow tubes. Remote sensing, without penetration of the vessel, is effected by means of ioniccoupling to the electrolytic mixture through membraneous materials impervious to blood.

United States Patent 1191 Davis 1451 July 16, 1974 BLOOD FLOW. DIAGNOSTIC METHOD [76] Inventor: Merlin Davis, 105 Columbia Ave.,

Pitman, NJ. 08071 [22] Filed: Aug. 10, 1972 [21] Appl. No.: 279,738

Related US. Application Data [62] Division ofSer. N0. 867,561,0ct. 20, 1969, Pm. N0.

[52] US. Cl....- 128/2.05 F, l28/2.1 E [51] Int. Cl A6lb 5/02 [58] Field of Search 324/65 R, 29, 30 R, 30 B; 204/195 R, 195 B, 195 M, 1 T; 73/194 E, 194 F; 128/205 F, 2.05 R, 2 E, 2.1 E

[5 6] References Cited UNlTED STATES PATENTS 3,151,052 9/1964 Arthur et al. 324/30 X 3,242,729 3/1966 Keller 324/30 X 3,250,987 5/1966 Okada et a1 324/30 B 3,529,591 9/1970 Schuette 128/205 F 3,572,315 3/1971 Cullen 128/2 E 3,580,239 5/1971 Watanabe 128/21 3,590,810 7/1971 Kopecky 204/195 M OTHER PUBLICATIONS N.B.S. Report No. 8,917, June 30, 1965.

Primary Examiner-Kyle L. Howell [57] ABSTRACT A diagnostic method intended primarily for the evaluation of velocity-related abnormalities in blood. These conditions are determined by sensing the inherent tendency of blood red cells to modulate the amplitude of an electric current at a distance from the electrodes.

Resulting variations in electrical impedance follow an invariable cube-root function of corpuscle velocity. Electrode configuration and placement are essential factors. The electrodes employed are specially adapted for the measurement of velocity in very small vesssels or hollow tubes. Remote sensing, without penetration of the vessel, is effected by means of ioniccoupling to the electrolytic mixture through membraneou's materials impervious to blood.

1 Claim, 8 Drawing Figures 1 BLOOD FLOW DIAGNOSTIC METHOD This application is adivision of application Ser. No. 867,561, filed Oct. 20, 1969, now Pat. No. 3,689,393.

The present invention relates, in general, to diagnostic methods capable of measuring physical manifestation which are responsive to the movement of erythrocytes, or blood red cells in the presence of an electric current. The response from this transducer conforms consistently to a simple law relating to the velocity of the erythrocytes. The degree of response, or sensitivity, depends in addition to the carrier current strength upon their number, age, oxygen transport and other related parameters, whether suspended naturally in the plasma of whole blood or in some other compatible electrolyte.

The present invention is an outgrowth of an investigation described in National Bureau of Standards Technical News Bulletin of Mar., I966, p. 38, entitled, Blood-flow Sensor. The rate of flow was reported as related to electrical conductivity. Tests were conducted in blood vesselswhich were large enough to insert a catheter. The catheter had a solid electrode mounted near the tip. The other electrode was placed on the subjects skin. A limit, however, has been found to the size of vessel applicable to this procedure. Electrodesof the limited area required for the smaller vessels fail to provide a flow-response signal. The present invention makes possible the sensing of blood-flow rate in small flow tubes as well as those of larger size. In addition, it permits this to be done without entering the vessel. Use with small flow-tubes also makes possible the construction of a diagnostic method for evaluating blood flow irregularities and the vitality of blood redcells per se with conveniently small blood specimens.

To carry out the principles of this invention certain prescribed physical conditions must be met in order to provide a requisite low-current density at the electrodes and a maximum interelectrode electrical impedance. These factors depend upon the size, kind and placement of these electrodes which carry the electrical current to and from a given electrolyte. This elect'rolyte must,howe ver, contain moving erythrocytes to be effective.

In addition to the foregoing prerequisites some electronic processing of the raw signal modulations .emanating from one of the electrodes which forms the sensing probe, is necessary in order to present the output in a useful form. For example, since the law governing the response'follows a cube-root function relative to the velocity of the erythrocytes, a unit may be added for cubing the detected amplitude modulations from the transducing probe. This would serve to linearize the final output and eliminate the need for use of a nonlinear meter scale. In so doing an output is obtainable which is directly proportional to the velocity of the erythrocytes flowing through a given blood vessel. Furthermore, if in addition, a normalization circuit is added, then comparative velocity measurements may be made between blood vessels and a specific or absolute velocity output signal, which is independent of the average carrier current, may be obtained if desired. The output signal would then equal to (Ae) /I, where (Ae) equals the cubed amplitude modulation, as detected, which is proportional to the velocity and I equals the average detected carrier current. This can be done by injection of a feed-back signal proportional to the average current I passing through the transducer to a normalizing divider unit ahead of the recorder or other utilization circuit, somewhat in the manner of automatic-volume-control circuits employed in the electronic art. The addition of the normalizing circuit is helpful for in vivo measurements in different loca tions where absolute velocities are required and occlusion is to be avoided for zero-flow adjustment. For some in vitro applications flow-rate measurement is not the primary objective. For example, if the flow of the red cells is maintained constant at some given velocity an electrical output is obtainable which is proportional to the several'parameters relating to the well-being of the erythrocytes, since they alone produce the primary flow-related response described. By passing measured volumes of centrifuged red cells immersed in saline through a flow-tube equipped with electrodes to be described, an index relating to red cell population is obtained.

Other more specific objectives include:

For in vivo applications:

a. Use in research concerning the extent of pulsations in arteries as they approach the proportions of arterioles. Research in this direction has been limited in the past by the available size of hollow-tube hypodermic needles and the ability to puncture such small vessels to obtain pressure variation indications.

b. Detection or measurement of blood flow in the eyes, pulp of the teeth, etc.

0. Determination of impairment to circulation, such as exists in frost-bite areas of the skin and around tumerous growths as compared with like areas in another similar portionof the body.

d. External monitoring of the amount of gasabsorbed by the blood, as in deep-sea diving operations.

For in vitro evaluations:

a. Comparisons between normal and pathologic blood at constant flow velocity, i.e., an activity index for the blood.

b. Rapid sedimentation rate measurements.

0. Blood red-cell population counting index using a measured volume of cells in physiological normalsa- -line.-

d. Study of the sluggishness of some red cells and their propensityto stagnate in the smaller vessels, such as the coronary arteries. For this purpose the diagnostic apparatus of FIG. 1 would be used and comparisons made between measured flow rates in different bore sized flow tubes while maintaining equal (7/5) ratios (see later discussion) and equal pumping pressures. (It should be mentioned here that modulations obtained in this system are not affected, at the amplification employed, by static pressure applied to electrolytes mixtures with blood red cells).

e. Gradual hemolysis of erythrocytes. This is possible because only intact'living blood-red cells are responsible for the flow-rate modulation effect.

f. Blood flow measurements in vitro, under controlled conditions, as an indirect method for thedetermination of changes in blood rheology due tocauses other than red-cell impairment.

Still other advantages will become apparent upon reference to the specifications and drawings, in which:

FIGS. 1 to 8 are diagramatic illustrations in simplified form in which FIG. 1 illustrates an in vitro, or clinical laboratory application of the invention for diagnostic use in testing small blood specimens for various pathologic conditions.

FIG. 2 is a fragmentary illustration of an alternative construction of a passive electrode unit shown as 14 in the upper portion of FIG. 1.

FIG. 3 is an enlarged alternative cross sectional illustration of the working or sensing electrode unit shown as 8 in the lower portion of FIG. 1.

FIG. 4 illustrates an instrument for'use with living subjects or in vivo application of the invention for detecting and measuring the blood-flow rate by external contact with the vessel or skin over it, especially adapted for use with very small vessels.

FIGS. 5 and 6 illustrate alternative constructions for the active working or sensing electrode unit 26 shown in the lower portion of FIG. 4.

FIGS. 7 and 8 are included to show the principles involved and to illustrate the necessity for considering specific relative dimensions between the various elements involved. This is not entirely obvious from the structural form alone, shown in the previous illustrations mentioned. FIG. 7 shows the skeletonized structure of the invention from the standpoint of established theory for comparison with the applicable equivalent electrical circuit shown in FIG. 8.

FIG. 1 is an illustration in simplified form of the present invention as adapted for in vitro, or clinical laboratory diagnostic applications. It combines a fluidtransport system 1 constructed from some electrical insulating material, preferably of some chemically inert plastic composition with blood red-cell compatibility, including a fluid mixture in the form of an emulsion, including an electrolyte (2). This may be a small specimen of whole blood obtained directly from a patient or it may be in the form of a fluid mixture made up as an emulsion of erythrocytes, or blood red-cells in some compatible electrolyte, such as physiological normalsaline. This fluid transport system 1 is provided with a reservoir or containing means 3 which acts as a source of supply of the electrolyte mixture 2. The fluid transport system 1 has a passageway opening from the containing means 3 in the form of a small bore tube 4 through which the electrolyte mixture 2 is forced to flow at controlled predetermined velocities as V,, indicated by the arrow 5. This is accomplished by some pumping means 43, known to the arts, as represented by arrows 6 indicating exerted pressure on the surface of the electrolyte mixture 2. At a position along the said passageway 4, at a prescribed minimum distance from the electrolyte supply container 3 is provided an opening or small aperture 7 in the wall of the flow passage way tube 4. An active or sensing electrode probe unit 8 includes an electrode 9 of electrical conducting material such as platinum, stainless steel, etc., having an attached conductor which is shown sealed in an insulating envelope 10 forming a complete enclosure except for one small aperture l1.This aperture is placed in a position corresponding with the opening 7 in the flow passageway 4. The envelope 10 including its aperture 11 is filled with some ionic conducting medium 12. This may be a simple salt bridge made by sucking a melted gel powder, such as agar, which is saturated with KC] or KNO solution, through the aperture 11 and then sealing the other end above the electrode 9 with a wax seal 13. i

On the other hand, a non-polarizable (Cu-Cu-SOJ) electrode unit would work equally as well. The important thing is to have an apparent electrode of very small size which virtually acts as a real electrode of large area. A second companion electrode unit 14 which may be identical in construction and material as described for the working or velocity sensing unit 8 is provided. It may be considered as the passive or reference electrode unit and is placed opposite an opening 15 in the electrolyte container or reservoir 3 to allow passage of ions from this electrode to the electrolyte in the reservoir 3 where the flow rate 0 is minimal as represented by arrow 16.

The electrical system 17 includes a source of electrical energy 18 for imposing a fraction of a volt across the current-carrying electrode units 8 and 14. This may be an alternating-current oscillator. The frequency required does not appear to be critical. A frequency of 2400 Hz proved satisfactory. When so excited, under the prescribed conditions of this invention, the moving erythrocytes in the electrolyte emulsion act upon the current waveform so as to increase its strength or modulate the amplitude in proportion to the cube-root of the flow-rate of these blood red-cells in the immediate vicinity of the opening 7 in the flow tube 4. These modulations may then be monitored and the output presented in useful form by any of the several means known to the electronic arts. This electrical system 17 may include, the-source of excitation 18 connected to the electrodes of units 8 and 14 by leads 20 and 19 respectively through a coupling network in the form, for example, of an electrical bridge, it may also include an amplitude modulation detector, all as represented in combination by unit 21. This unit 21 may operate into a recorder, galvanometer, on other'output 22 directly, or a cubing unit 23 may be incorporated ahead of the amplifier to provide a linear output (see Function Generator Derives Output Optically," Design News, Jan. 6, 1969, p. 30).

FIG. 2 shows an alternative electrode construction 14a which may be used to replace the passive electrode unit 14 with its ionic entrance to the electrolyte 11 in the container or reservoir 3. This is simply a metallic I conductor electrode 9 of area equal to that of passive electrode unit 14 in contact-with the electrolyte 2 with a lead 19 extending through the walls of the fluid source container 3. FIG. 3 illustrates an alternative modification 8a for the working or active sensing unit 8 which has a membrane film 24 interposed between the opening 11 in the envelope 10 and that of the electrolyte flow tube 7. This membrane may be a piece of cellophane dialysis sheeting which allows free transfer of ions to and from the electrode 9 and the electrolyte 2 but is impervious to blood. I

The form of the invention FIG. 4, which is analogous to FIG. 1 in many respects, shows the application of 2 these principles for use with living subjects, i.e., use in vivo. Here the fluid transport system 1 of FIG. 1 becomes the sheathed vascular circulatory system of the body, indicated by numeral 25 of FIG. 4. This system -is comprised of vessels made up of hollow tubes which may range from an inch in diameter for the large aorta to the microscopic capillaries. The transported fluid, naturally, is the blood in this case which is pumped through the system by the heart. (In the circulatory system the total cross-sectional area gradually increases as we go from aorta to arteries to arterioles. At

the point where arterioles break into a profusion of capillaries, the area suddenly increases tremendously, with a sudden marked slowing of the rate of flow. Correspondingly, as the capillaries join to form venules, or little veins and these in turn unite into larger vessels, the total cross-sectional area diminishes. and the rate of flow increases again The speed of flow in the large veins almost attains that of the large arteries r The sensing electrode unit or probe 26 is constructed much the same as that in FIG. '1 except that the tip is extended as shown 27 like a hollow insulated needle with the ion conducting gelextending somewhat beyond the tip. The electrode unit tip is placed in contact with the skin 28, as shown, directlyover the vessel 29 where the flow rate V, indicated by arrow 30 is to be measured. It will be noted that membrane 24 of the alternate electrode unit construction 8a of FIG. 3 is somewhat like the skin tissues between the tip of the electrode unit 26 and the vessel 29 whose blood flow is to be measured. Blood vessel 29 corresponds with the passageway flow tube 4 of the fluid transport system of FIG. 1 and arrow 30 indicates the velocity V, which is to be measured in blood vessel 29. A passive electrode unit is shown in the form of a large area metal conducting plate 31. This corresponds with the passive electrode unit 14 which is shown as coacting with the slow moving electrolyte 2 in supply container 3 of FIG. 1. In FIG. 4 passive electrode 31 is shown mounted directly in contact with the skin 28 over a capillary bed 32 with an intervening conducting pathway to the body circulatory system 25, where velocity V0 is minimal, as indicated by arrow 33, at a considerable distance away from the active working or sensing electrode unit 26. The broken line 34 is intended to indicate the intervening distance along the subjects body. For this purpose the passive electrode 31 may be placed against an ear lobe, finger, toe or heel. The electronic units 35 are the same as shown in FIG. 1 except for the addition, where required, of a divider for'sensitivity or scale factor normalization circuit 36. In both cases the modulation detector may be in the form of a synchronous detector.

A special application exists for this invention for determining the degree of gas saturation in the blood of deep-sea divers. For thispurpose, this synchronous detector would be phased by 90 from non-reactive settings, since the peak cavitation effects have been found to lag the blood flow-rate effect of the erythrocytes by this angle.

FIG. 5 shows an alternative form 26a of sensing electrodeunit 26 of FIG. 4. The envelope in this case is constructed from a flexible plastic composition with electrical insulating properties comprising the domeshaped portion as shown 37, or equivalent form, for holding the metal electrode 9 and through which its lead 20 passes. Dome portion 37 is attached to a flat strip 38 of similar material, forming a complete enclosure for the electrode 9 except for a small opening 11 in the flat portion where the cavity is formed. This cavity 12 is filled with an ionic conducting gel, as before, extending through the hole 11. Straps 39 and 40, or other means, may be provided for use in fastening the unit 26a on some portion of the body to hold it firmly in position so that opening'll is positioned over the vessel or vessels in question.

FIG. 6 shows a cross-sectional view of another alternative form of sensing electrode unit 26!). In this unit the ionic conducting bridge 41 between the electrode 9 and electrolyte through flesh 28 is partially unsupported and the insulating electrode holder 42 extends only part way down the ionic conducting bridge 41 which is self-supporting and may be arranged for movable extension. It may be formed from cellular material, a porous wick or stiff gel-like material.

This funnel shaped ionic conductor 41 concentrates the ions as they are transferred along its converging length and the boundry ionic conducting layer between its tip and the electrolyte. This boundry layer constitutes the vessel wall or the flesh immediately above it 28 in vivo as shown in FIG. 4. In in vitro use, FIG. I, this boundry layer is the opening 7 in the insulating flow tube 4 which is plugged with the ionic conducting gel 12 or the film 24, of FIG. 3, each impervious to blood but free to conduct ions.

It was stated earlier in the specifications that the blood red-cell flow-rate, assuming laminar flow, amplitude modulates the electric current wave form, if alternating current, according to a precise cube-root law, provided however certain prescribed conditions are met. It is clear that these definite definable results are un-obvious merely from inspection-of the method of construction of the system, as shown in FIG. 1, but must be defined otherwise in terms of specific relative dimension limitations. For a better understanding of these requirements refer to FIG. 7 and 8 which should be considered together and compared.

FIG. 7 shows a conventionalized sketch representing the fluid transport system such as .1 in FIG. 1, flowing electrolyte 2 at velocity V0 (16) and V (5), the electrodes l4 and 8 for passive and sensing or active electrode, respectively, and a source 18 and sink or ground 44 for the electric-current circuit. FIG. 8 represents an idealized equivalent electrical circuit as applied to structure FIG. 7. The broken dividing lines a-b and a'b separate the electro-chemically active portion, which occurs at the immediate interface of the metallic electrodes with the electrolyte boundry layers in both FIGS. 7 and 8. The capacitance marked Cdb/Z in FIG. 8 is correspondingly indicated in FIG. 7 by the dotted double lines (db) representing the conventionally understood Helmholtz double stationery-layers of ions which form, in effect, the action of an electrical capacitance. The impedance at each of these electrode boundry interfaces Zdb/2 combines the Faraday or electrochemical impedance Xf/2 along with the reactance presented by the effective capacitance of the doublelayer (db). The interelectrode resistance in the body of the electrolyte represented by R depends in part upon the dimensions of the fluid-flow transport system 1. The modulation of the current in the electrolyte of the container is represented by the very small variable resistance Ar, corresponding to the almost static flowrate V0 and the considerably larger variable resistance Ar, corresponding with the velocity V, in the passageway of the fluid transport system near the opening (7) opposite the sensing electrode unit aperture 11, or virtual electrode, as shown in FIG. 1. The amplitude modulationAr, which increases with velocity, does so as a cube-root function attributable to the living, blood redcells when in motion. I

The problem is to provide a means for minimizing the electrode effects" relative to the floweffects due to the red-cell movement in the body of the electrolyte near the sensing electrode Ar, by employing a high im- 7 pedance inter-electrode pathway relative to the impedance due to the electrode-effects Zdb and minimizing Ar This is accomplished if:

V0,- R Zdb, where R f(T/ci) and V Zdb =fA The! A a)??? 1 Dimensionally speaking, this means that the electrodes should be of substantial area to provide a low current density at the applied potential. (Satisfactory operation at a minimum real electrode area of 3 sq. mm with a fraction of a volt excitation between the electrodes was observed). The cross sectional area of the container should be at least 8 times t hat of the passageway or flow tube bore. A ratio for (l/a of I50 and over has been found acceptable.

Under these limitations an interelectrode impedance of 9,000 ohms or over for whole-blood was found satisfactory and provides a criterion for spacing the electrodes in vivo, as shown in FIG. 4.

It is to be understood that flow-rate measurements may be made in large bore flow tubes or large blood vessels by inserting a metallic sensing electrode directly into the flow-tube in the region to be measured. The electrode would be in the form of a single electrode catheter for use in vivo. Comparable reduction of metal electrodes for small-bore flow tubes, such as required for the diagnostic instrument of FIG. 1 or small blood-vessels in mechanically feasible but electrically inoperative because of the high electrode effect impedances which result from the use of such microelectrodes. It is therefore the special purpose of this invention to provide in cooperative combination with the other elements making up the working assembly the special electrode units such as shown in FIGS. 1, 3, 4,

5, and 6 which make possible high-impedance flow-rate measurements in the smaller flow tubes and blood vessels because the micro-ionic conducting aperture placed in or near the flow stream acts virtually as though it were a real electrode of large area and low impedance.

It should also be noted that without dimensional considerations the structure shown in FIG. 1 might pass for polarographic devices employed for chemical analysis. In such instruments one saturated or depolorized electrode acts as a reference or /2 cell of constantpotential, regardless of the magnitude of the current, while the companion polorized [2 cell, which is usually placed in a moving stream of the electrolyte in question, is designed-to accent rather then minimize the electrode effect which is the quantity, in the form of current vs voltage relationship, to be measured rather than the movement of the electrolyte. This movement is only incidental to the operation of the working micro-electrode or equivalent polarized probe employed. The electrodes are also closely spaced to minimize the impedance in the body of the electrolyte. In other words, diametrically opposite relative dimensional proportions then required by this invention, where a relatively high impedance is desired in the body of the electrolyte. The fact is, if two reference /2 cell electrodes were used rather than but one reference cell electrode, as here proposed as an alternative arrangement in this invention, no polarographic action could take place.

Some electrically operated blood red-cell counting devices also employ electrodes. These depend in principle upon the increase of resistance as the cells pass between a restricted passageway between the electrodes. This is due to the poor conductive properties of the red cells relative to their surrounding medium, in this case physiological normal saline. It is to be noted that in this invention the degree of response at a given flow-rate increased and the resistance decreases as the number of red-cells become more numerous.

It will be apparent that the embodiments shown are only exemplary and that various modifications can be made in construction and arrangement within the scope of invention as defined in the appended claims.

What is claimed is:

l. A method for determining the velocity and velocity-related characteristics of erythrocytes while suspended within a flowing stream of an electrolyte, to form a mixture thereof, said flowing stream having at least one portion moving at a relatively slower rate than other portions, a condition found within the circulatory system of a living body; providing by said method an electrical output signal which increases in proportion to the cube-root of the velocity of said erythrocytes; said method comprising the steps of:

a. passing an electric current from a source of energy between a more quiescent flowing portion of the stream and a portion, the flow rate of which is to be determined;

b. effecting transfer of said electric current from said source of energy to said electrolyte mixture with non-polarizing, ion-coupled electrode means, including chemically inert electrodes provided with sufficiently large effective surface areas to so reduce the current density at the surfaces of the said electrodes whereby a minimum electrical impedance at the electrode interfaces is obtained;

c. selectively positioning said electrode probe means along the said flow stream to-provide said ionic coupling with the said electrolyte mixture within the flow stream whereby an inter-electrode impedance is provided which is sufficiently large, relative to that obtained at the said electrode interfaces to permit the said required cube-root functional relationship to become effective;

d. monitoring the said cube-root functional modulations produced in the-said electric current which results from the electrical impedance variations in proximity to the said electrode probe means caused by the reaction to movement of the said erythrocytes in the presence of the said electric current;

, e. converting the said monitored electrical output signals into utilizable form. 

1. A method for determining the velocity and velocity-related characteristics of erythrocytes while suspended within a flowing stream of an electrolyte, to form a mixture thereof, said flowing stream having at least one portion moving at a relatively slower rate than other portions, a condition found within the circulatory system of a living body; providing by said method an electrical output signal which increases in proportion to the cube-root of the velocity of said erythrocytes; said method comprising the steps of: a. passing an electric current from a source of energy between a more quiescent flowing portion of the stream and a portion, the flow rate of which is to be determined; b. effecting transfer of said electric current from said source of energy to said electrolyte mixture with non-polarizing, ioncoupled electrode means, including chemically inert electrodes provided with sufficiently large effective surface areas to so reduce the current density at the surfaces of the said electrodes whereby a minimum electrical impedance at the electrode interfaces is obtained; c. selectively positioning said electrode probe means along the said flow stream to provide said ionic coupling with the said electrolyTe mixture within the flow stream whereby an interelectrode impedance is provided which is sufficiently large, relative to that obtained at the said electrode interfaces to permit the said required cube-root functional relationship to become effective; d. monitoring the said cube-root functional modulations produced in the said electric current which results from the electrical impedance variations in proximity to the said electrode probe means caused by the reaction to movement of the said erythrocytes in the presence of the said electric current; e. converting the said monitored electrical output signals into utilizable form. 